US2004198752A1PendingUtilityA1
Method for inhibiting retinoid skin damage
Priority: Feb 12, 2001Filed: Apr 14, 2004Published: Oct 7, 2004
Est. expiryFeb 12, 2021(expired)· nominal 20-yr term from priority
A61P 35/00A61P 17/10A61P 17/00A61K 31/519A61K 31/517A61K 31/203A61P 17/06A61P 17/02A61K 31/07A61K 8/4953A61Q 19/08A61K 8/671A61K 31/11A61P 17/16A61K 8/67A61K 8/49A61Q 19/00
40
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Claims
Abstract
Erb inhibitors used in combination with retinoids are effective to prevent skin injury otherwise caused by retinoids alone. A method of treating skin aging and similar skin disorders comprises administering retinoids in combination with erb inhibitors of the general formula where E 1 , E 2 , and E 3 include halo, aryl is an alkylcarbonyl or alkenylcarbonyl, and alkoxy is lower alkoxy optionally substituted with amino groups.
Claims
exact text as granted — not AI-modified1 - 11 . (canceled)
12 A method for alleviating retinoid induced skin injury comprising administering an effective amount of an erb inhibitor to a patient in need thereof.
13 A method according to claim 12 in which said erb inhibitor is a compound represented by the formula
wherein Q is
p is 0 or 1;
X is —D—E—F and Y is —SR 4 , —OR 4 , —NHR 3 , or hydrogen, or X is —SR 4 , —OR 4 , —NHR 3 , or hydrogen, and Y is —D—E—F;
D is
or absent;
E is
F is
provided that when E is
D is not
R 1 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 2 , R 3 , and R 4 are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 —(C 1 -C 6 ) alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n —-pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n -imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino, —(CH 2 ) n —N-hexahydroazepine or substituted C 1 -C 6 alkyl, wherein the
substituents are selected from OH, —NH 2 , or —N—B,
are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n OH, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 —(C 1 -C 6 ) alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n —N-pyridyl, —(CH 2 ) n -imidazoyl, or —(CH 2 ) n —N-imidazoyl;
E 1 , E 2 , and E 3 are independently halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, nitro, C 1 -C 6 perfluoroalkyl, hydroxy, C 1 -C 6 acyloxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 3 -C 8 cycloalkyl), —N(C 3 -C 8 cycloalkyl) 2 , hydroxymethyl, C 1 -C 6 acyl, cyano, azido, C 1 -C 6 thioalkyl, C 1 -C 6 sulfinylalkyl, C 1 -C 6 sulfonylalkyl, C 3 -C 8 thiocycloalkyl, C 3 -C 8 sulfinylcycloalkyl, C 3 -C 8 sulfonylcycloalkyl, mercapto, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 2 -C 4 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 4 alkynyl;
R 5 is hydrogen, halogen, C 1 -C 6 -perfluoroalkyl, 1,1-difluoro(C 1 -C 6 )alkyl, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n -piperazinyl, —(CH 2 ) n -piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino,
—CH═CH—(C 1 -C 6 )alkyl, —(CH 2 ) n —N-hexahydroazepine, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl) 2 , -1-oxo(C 1 -C 6 )alkyl, carboxy, (C 1 -C 6 ) alkyloxycarbonyl, N—(C 1 -C 6 )alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z 1 , Z 2 , Z 3 or a monocyclic heteroaryl group, and each C 1 -C 6 alkyl group can be substituted with —OH, —NH 2 or —NAB, where A and B are as defined above, R 6 is hydrogen or C 1 -C 6 alkyl; and
n is 1 to 4, p is 0 and 1, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
14 A method according to claim 13 wherein the erb inhibitor is 5-(4-methyl-piperazin-1-yl)-pent-2-ynoic acid [4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide or N 4 -(3-bromo-phenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine.
15 A method according to claim 12 wherein said erb inhibitor is a compound represented by the Formula
wherein X is —D—E—F and Y is —SR 4 , halogen, —OR 4 , —NHR 3 , or hydrogen, or X is —SR 4 , halogen, —OR 4 , —NHR 3 , or hydrogen, and Y is —D—E—F;
D is
or absent;
E is
F is
provided that when E is
D is not
R 1 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 2 , R 3 , and R 4 are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N1-piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n -imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino, —(CH 2 ) n —N-hexahydroazepine or substituted C 1 -C 6 alkyl, wherein
the substituents are selected from —OH, —NH 2 , or
A and B are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n OH, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N-piperazinyl[N 4 —(C 1 -C 6 -)alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n —N-pyridyl, —(CH 2 ) n -imidazoyl, or —(CH 2 ) n —N-imidazoyl;
Z 1 , Z 2 , or Z 3 are independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, nitro, C 1 -C 6 perfluoroalkyl, hydroxy, C 1 -C 6 acyloxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 3 -C 8 cycloalkyl), —N(C 3 -C 8 cycloalkyl) 2 , hydroxymethyl, C 1 -C 6 acyl, cyano, azido, C 1 -C 6 thioalkyl, C 1 -C 6 sulfinylalkyl, C 1 -C 6 sulfonylalkyl, C 3 -C 8 thiocycloalkyl, C 3 -C 8 sulfinylcycloalkyl, C 3 -C 8 sulfonylcycloalkyl, mercapto, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 2 -C 4 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 4 alkynyl;
R 5 is hydrogen, halogen, C 1 -C 6 -perfluoroalkyl, 1,1-difluoro(C 1 -C 6 )alkyl, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n -piperazinyl, —(CH 2 ) n -piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino,
—CH═CH—(C 1 -C 6 )alkyl, —(CH 2 ) n —N-hexahydroazepine, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl) 2 , -1-oxo(C 1 -C 6 )alkyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, N—(C 1 -C 6 )alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z 1 , Z 2 , Z 3 or a monocyclic heteroaryl group, and each C 1 -C 6 alkyl group above in R 5 can be substituted with —OH, —NH 2 or —NAB, where A and B are as defined above, R 6 is hydrogen or C 1 -C 6 alkyl; R 13 is hydrogen or halogen; and
n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
16 A method according to claim 15 wherein said compound is N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide or N-[4-(3-bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide.
17 A method for alleviating the dermal side effects associated with the topical administration of retinoids comprising the administration of an effective amount of an erb inhibitor to a patient in need thereof.
18 A method according to claim 17 in which said erb inhibitor is a compound represented by the formula
wherein Q is
p is 0 or 1;
X is —D—E—F and Y is —SR 4 , —OR 4 , —NHR 3 , or hydrogen, or X is —SR 4 , —OR 4 , —NHR 3 , or hydrogen, and Y is —D—E—F;
D is
or absent;
E is
F is
provided that when E is
D is not
R 1 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 2 , R 3 , and R 4 are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 -(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n -imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino, —(CH 2 ) n —N-hexahydroazepine or substituted C 1 -C 6 alkyl, wherein the
substituents are selected from OH, —NH 2 , or
A and B are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n OH, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 —(C 1 -C 6 ) alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n —N-pyridyl, —(CH 2 ) n -imidazoyl, or —(CH 2 ) n —N-imidazoyl;
E 1 , E 2 , and E 3 are independently halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, nitro, C 1 -C 6 perfluoroalkyl, hydroxy, C 1 -C 6 acyloxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 3 -C 8 cycloalkyl), —N(C 3 -C 8 cycloalkyl) 2 , hydroxymethyl, C 1 -C 6 acyl, cyano, azido, C 1 -C 6 thioalkyl, C 1 -C 6 sulfinylalkyl, C 1 -C 6 sulfonylalkyl, C 3 -C 8 thiocycloalkyl, C 3 -C 8 sulfinylcycloalkyl, C 3 -C 8 sulfonylcycloalkyl, mercapto, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 2 -C 4 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 4 alkynyl;
R 5 is hydrogen, halogen, C 1 -C 6 -perfluoroalkyl, 1,1-difluoro(C 1 -C 6 )alkyl, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n -piperazinyl, —(CH 2 ) n -piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino,
—CH═CH—(C 1 -C 6 )alkyl, —(CH 2 ) n —N-hexahydroazepine, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl) 2 , -1-oxo(C 1 -C 6 )alkyl, carboxy, (C 1 -C 6 ) alkyloxycarbonyl, N—(C 1 -C 6 )alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z 1 , Z 2 , Z 3 or a monocyclic heteroaryl group, and each C 1 -C 6 alkyl group can be substituted with —OH, —NH 2 or —NAB, where A and B are as defined above, R 6 is hydrogen or C 1 -C 6 alkyl; and
n is 1 to 4, p is 0 and 1, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
19 A method according to claim 17 wherein the erb inhibitor is
5-(4-methyl-piperazin-1-yl)-pent-2-ynoic acid [4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide or N 4 -(3-bromo-phenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine.
20 A method according to claim 17 wherein said erb inhibitor is a compound represented by the Formula
wherein X is —D—E—F and Y is —SR 4 , halogen, —OR 4 , —NHR 3 , or hydrogen, or X is —SR 4 , halogen, —OR 4 , —NHR 3 , or hydrogen, and Y is —D—E—F;
D is
or absent;
E is
F is
provided that when E is
D is not
R 1 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 2 , R 3 , and R 4 are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n -imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino, —(CH 2 ) n —N-hexahydroazepine or substituted C 1 -C 6 alkyl, wherein
the substituents are selected from —OH, —NH 2 , or
A and B are independently hydrogen, C 1 -C 6 alkyl, —(CH 2 ) n OH, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n —N-piperazinyl, —(CH 2 ) n —N 1 -piperazinyl[N 4 —(C 1 -C 6 -) alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n —N-pyridyl, —(CH 2 ) n -imidazoyl, or —(CH 2 ) n —N-imidazoyl;
Z 1 , Z 2 , or Z 3 are independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, nitro, C 1 -C 6 perfluoroalkyl, hydroxy, C 1 -C 6 acyloxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH(C 3 -C 8 cycloalkyl), —N(C 3 -C 8 cycloalkyl) 2 , hydroxymethyl, C 1 -C 6 acyl, cyano, azido, C 1 -C 6 thioalkyl, C 1 -C 6 sulfinylalkyl, C 1 -C 6 sulfonylalkyl, C 3 -C 8 thiocycloalkyl, C 3 -C 8 sulfinylcycloalkyl, C 3 -C 8 sulfonylcycloalkyl, mercapto, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 2 -C 4 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 4 alkynyl;
R 5 is hydrogen, halogen, C 1 -C 6 -perfluoroalkyl, 1,1-difluoro(C 1 -C 6 )alkyl, C 1 -C 6 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n -piperazinyl, —(CH 2 ) n -piperazinyl[N 4 —(C 1 -C 6 )alkyl], —(CH 2 ) n —N-pyrrolidyl, —(CH 2 ) n -pyridinyl, —(CH 2 ) n —N-imidazoyl, —(CH 2 ) n —N-morpholino, —(CH 2 ) n —N-thiomorpholino, —
—(CH 2 ) n —N-hexahydroazepine, —(CH 2 ) n NH 2 , —(CH 2 ) n NH(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl) 2 , -1-oxo(C 1 -C 6 )alkyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, N—(C 1 -C 6 )alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z 1 , Z 2 , Z 3 or a monocyclic heteroaryl group, and each C 1 -C 6 alkyl group above in R 5 can be substituted with —OH, —NH 2 or —NAB, where A and B are as defined above,
R 6 is hydrogen or C 1 -C 6 alkyl; R 13 is hydrogen or halogen; and n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
21 A method according to claim 17 wherein said compound is N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide or N-[4-(3-bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide.Join the waitlist — get patent alerts
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